Methods for treating endoleaks during endovascular repair of abdominal aortic aneurysms

ABSTRACT

Disclosed are methods for treating endoleaks arising from endovascular repair of abdominal aortic aneurysms. The disclosed methods involve the in situ sealing of endoleaks after placement of an endovascular prostheses in the abdominal aorta. Sealing of endoleaks is achieved by injection of either a biocompatible polymer or prepolymer fluid composition into the endoleak which composition in situ solidifies to seal the leak. Preferably, the biocompatible fluid composition comprises a contrast agent to allow the clinician to visualize the sealing process.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention is directed to methods for treating endoleaks arisingfrom endovascular repair of abdominal aortic aneurysms. Specifically,the methods of this invention involve the in situ sealing of endoleaksafter placement of an endovascular prostheses in the abdominal aorta.Sealing of endoleaks is achieved by injection of either a biocompatiblepolymer or prepolymer fluid composition at the site of the endoleakwhich composition in situ solidifies and adheres to the vascular and/orprosthetic wall to seal the leak. Preferably, the biocompatible fluidcomposition comprises a contrast agent to allow the clinician tovisualize the sealing process.

2. References

The following publications, patent applications and patents are cited inthis application as superscript numbers:

1 May, et al., “Concurrent Comparison of Endoluminal Versus Open Repairin the Treatment of Abdominal Aortic Aneurysms: Analysis of 303 Patientsby Life Table Method”, J. Vase. Surg. 27(2):213-221 (1998)

2 White, et al., J. Endovasc. Surg., 3:124-125 (1996)

3 Marty, et al., “Endoleak After Endovascular Graft Repair ofExperimental Aortic Aneurysms: Does Coil Embolization with Angiographic“Seal” Lower Intraaneursymal Pressure”, J. Vasc. Surg., 27(3):454-462(1998)

4 Money, et al., “Perioperative Charge Comparison and EndovascularAbdominal Aortic Aneurysm Repair”, JPV 1.1-1.2, Presented at the 6^(th)Annual Symposium on Current Issues and New Techniques in InterventionalRadiology at New York, N.Y. in November, 1998

5 Beebe, et al., “Current Status of the United States Vanguard™Endograft Trial”, JPVA 2.1-2.3, Presented at the 6^(th) Annual Symposiumon Current Issues and New Techniques in Interventional Radiology at NewYork, N.Y. in November, 1998

6 Hopkinson, et al., “Current Critical Problems, New Horizons andTechniques in Vascular and Endovascular Surgery”, JPIII 4.1-4.2,Presented at the 6^(th) Annual Symposium on Current Issues and NewTechniques in Interventional Radiology at New York, N.Y. in November,1998

7 Kinugasa, et al., “Direct Thrombosis of Aneurysms with CelluloseAcetate Polymer”, J. Neurosurg., 77:501-507 (1992)

8 Greff, et al., U.S. Pat. No. 5,667,767 for “Novel Compositions for Usein Embolizing Blood Vessels”, issued Sep. 16, 1997

9 Greff, et al., U.S. Pat. No. 5,580,568 for “Cellulose DiacetateCompositions for Use in Embolizing Blood Vessels”, issued Dec. 3, 1996

10 Kinugasa, et al., “Early Treatment of Subarachnoid Hemorrhage AfterPreventing Rerupture of an Aneurysm ”, J. Neurosurg., 83:34-41 (1995)

11 Kinugasa, et al., “Prophylactic Thrombosis to Prevent New Bleedingand to Delay Aneurysm Surgery ”, Neurosurg., 36:661 (1995)

12 Taki, et al., “Selection and Combination of Various EndovascularTechniques in the Treatment of Giant Aneurysms”, J. Neurosurg., 77:37-42(1992)

13 Evans, et al., U.S. patent application Ser. No. 08/802,252 for “NovelCompositions for Use in Embolizing Blood Vessels”, filed Feb. 19, 1997.

14 Castaneda-Zuniga, et al., Interventional Radiology, in VascularEmbolotherapy, Part 1, 1:9-32, Williams & Wilkins, Publishers (1992)

15 Rabinowitz, et al., U.S. Pat. No. 3,527,224, for “Method ofSurgically Bonding Tissue Together”, issued Sep. 8, 1970

16 Hawkins, et al., U.S. Pat. No. 3,591,676, for “Surgical AdhesiveCompositions”, issued Jul. 6, 1971

17 Parodi, “Endovascular AAA Stent Grafts: Technology, Training andProper Patient Selection, JPVA 1.1-1.2 Presented at the 6^(th) AnnualSymposium on Current Issues and New Techniques in InterventionalRadiology at New York, N.Y. in November, 1998

All of the above publications, patent applications and patents areherein incorporated by reference in their entirety to the same extent asif each individual publication, patent application or patent wasspecifically and individually indicated to be incorporated by referencein its entirety.

STATE OF THE ART

Abdominal aortic aneurysms (AAA) represents a serious medical challengeand, when left untreated, eventual rupture of the aneurysm hassignificant morbidity associated therewith. When feasible, open surgeryto repair the aortic aneurysm has been shown to be clinicallysuccessful.¹ However, open surgery is often not feasible especially inpatients suffering from severe cardiac disease, renal disease or otherconditions which contra-indicate open surgery. For example, conventionalexposure of the infrarenal aorta necessitates a large abdominalincision, mobilization of the abdominal viscera, and retroperitonealdissection which are associated with complications such as renalfailure, pseudoaneurysms and bleeding. Infrarenal aortic clamping isalso associated with an increased cardiac demand including an increasein left ventricular end diastolic volume and may be related to cardiacmortality.

Less invasive methods for treating abdominal aortic aneurysms avoid manyof these problems and additionally result in reduced patient discomfort,reduced hospital stays and reduced care intensity.⁵ Endovascular graftshave been investigated as one example of a less invasive method for thetreatment of aneurysmal aortic disease. When compared to open surgery,endovascular grafting provides similar perioperative mortality ratesnotwithstanding the fact that endovascular grafting is often performedwith individuals who are not candidates for open surgery due to one ormore medical conditions which preclude such surgery.^(1,4) One of themain concerns regarding endovascular grafting is the continued bloodflow into the aneurysm after grafting which blood flow is termed in theart as an endoleak.² Endoleaks have been reported in about 7 and 37% ofendovascular aortic aneurysm repairs³ with some reports placing thisnumber as high as 44%.

Specifically, endovascular grafting requires catheter placement of anendovascular prostheses at the abdominal aortic aneurysm site. Endoleaksarising after such grafting may be caused by incomplete sealing betweenthe endovascular prosthesis and the aortic wall or by defects within theendovascular prostheses. In addition, back bleeding from patent lumbarand inferior mesenteric arteries following placement of the endovascularprostheses in the aorta has also been recited as a potential cause ofendoleaks.⁶ There is uniform agreement that large endoleaks that lead toaneurysm enlargement necessitate treatment in order to prevent aneurysmrupture. It is also reported that the size of the endoleak does notappear to be a relevant factor for pressure transmission into theaneurysm.³

There are a variety of treatment regimens for endoleaks reported in theliterature including endovascular repair by placement of additionalstents within the prostheses as well as insertion of metallic coils intothe aneurysm space to induce thrombosis therein. The goal of suchtreatments is complete exclusion of the aneurysm from systemic bloodflow. While complete exclusion is desirable, a secondary goal is toreduce intraaneursymal pressure (IAP) from blood flow into the aneurysmto acceptable levels thereby inhibiting the likelihood of rupture. Incases where no endoleaks arose after endovascular grafting, the mean IAPhas been reported to be reduced by about 65%. However, when endoleaksarise, it is reported that the mean IAP, while initially decreasingsignificantly, stabilized after a week at a reduction of only 22%.Moreover, the use of coils to induce thrombosis and thereby reduce IAPdid not have any significant impact on the IAP.

In view of existing problems associated with endovascular repair ofendoleaks, the accepted treatment for these endoleaks is open surgery.However, the mortality rates for open surgery of endoleaks is higherthan either initial open surgery for the abdominal aortic aneurysm orfor the initial endovascular repair of the aneurysm.

In view of the above, reliable endovascular methods to inhibit endoleaksafter endovascular graft repair of abdominal aortic aneurysms isdesirable.

SUMMARY OF THE INVENTION

This invention is directed to methods for treating endoleaks arisingfrom endovascular repair of abdominal aortic aneurysms. These methodsprovide for delivery of a fluid composition to the sites of endoleaks inthe abdominal aorta which fluid composition, in situ, forms a coherentsolid mass which adheres to vascular and/or prosthetic wall to seal theendoleak.

In a preferred embodiment, the fluid composition comprises abiocompatible polymer, a biocompatible solvent and a contrast agent toallow the clinician to visualize the procedure. In a further preferredembodiment, the contrast agent is a water insoluble contrast agentcharacterized by having an average particle size of about 10 μm or less.

In another preferred embodiment, the fluid composition comprises abiocompatible prepolymer and a contrast agent which, again, is employedto allow the clinician to visualize the procedure. In a furtherpreferred embodiment, the contrast agent is a water insoluble contrastagent characterized by having an average particle size of about 10 μm orless.

Accordingly, in one of its method aspects, this invention provides amethod for sealing endoleaks in a patient arising from endovascularrepair of abdominal aortic aneurysms which method comprises:

identifying one or more endoleaks in a patient treated for an abdominalaortic aneurysm with a endovascular prosthesis; and

delivering through a microcatheter to the site or sites of the endoleakin said patient a sufficient amount of a fluid composition underconditions wherein the fluid composition forms a coherent adhesive massin situ at said site or sites thereby sealing the endoleaks.

Methods further comprising the step of delivering a detectable agent,such as a contrast agent, through the catheter after it has beeninserted into the artery and detecting the agent to confirm that thecatheter has the proper placement prior to delivery of the fluidcomposition to the site of the endoleak are also provided.

In another of its method aspects, this invention is directed to a methodfor treating abdominal aortic aneurysms in a patient which methodcomprises:

identifying an abdominal aortic aneurysm in a patient;

endovascularly repairing said aneurysm by catheter delivery of anendovascular prosthesis to the site of said aneurysm thereby inhibitingblood flow into the aneurysm;

identifying the presence of endoleaks;

delivering to the site or sites of endoleaks in said patient asufficient amount of a fluid composition under conditions wherein thefluid composition forms a coherent mass in situ which adheres to thewalls of the vascular site and/or prosthesis thereby sealing theendoleaks.

This invention is also directed to kits of parts for use in endovasculartreatment of aneurysms in a patient including sealing of endoleaksarising from such repair. In one embodiment, this kit comprises thefollowing components:

(a) a fluid composition which forms a coherent mass in the presence ofblood which mass adheres to the vascular surface and/or the surface ofthe endovascular prosthesis;

(b) a catheter suitable for delivering the fluid composition to anendoleak site formed from endovascular repair of an aneurysm; and

(c) a catheter suitable for delivering an endovascular prosthesis to theaneurysm.

In a preferred embodiment, this kit further comprises an endovascularprosthesis.

In another embodiment, this kit comprises the following components:

(a) a fluid composition which forms a coherent mass in the presence ofblood which mass adheres to the vascular surface and/or the surface ofthe endovascular prosthesis;

(b) a catheter suitable for delivering the fluid composition to anendoleak site formed from endovascular repair of an aneurysm; and

(c) an endovascular prosthesis.

In a preferred embodiment, this kit further comprises a cathetersuitable for delivering an endovascular prosthesis to the aneurysm.

DETAILED DESCRIPTION OF THE INVENTION

This invention is directed to novel methods for sealing endoleaks in apatient which methods deliver endovascularly a fluid composition to thesite of the endoleak which composition solidifies in situ to seal theendoleak. Specifically, the fluid compositions used herein provide forformation of a coherent adhesive mass which forms in situ therebysealing endoleaks thereby overcoming complications heretofore associatedwith such leaks.

However, prior to discussing this invention in further detail, thefollowing terms will first be defined:

The term “sealing an endoleak” refers to a process wherein a fluidcomposition is injected at the site of the endoleak arising, forexample, at or adjacent the site of an abdominal aortic aneurysm treatedwith an endovascular prosthesis. Any endoleak can be treated in themethods of this invention including endoleaks arising, for example, fromincomplete sealing between the endovascular prosthesis and the aorticwall, from defects within the endovascular prosthesis, or fromretrograde flow from patent lumbar and inferior mesenteric arteriesfollowing placement of the endovascular prosthesis in the aorta.

The term “biocompatible polymer” refers to polymers which, in theamounts employed, are non-toxic, chemically inert, and substantiallynon-immunogenic when used internally in the patient and which aresubstantially insoluble in blood. Suitable biocompatible polymersinclude, by way of example, cellulose acetates^(7,10-11) (includingcellulose diacetate⁹), ethylene vinyl alcohol copolymers^(8,12),hydrogels (e.g., acrylics), polyacrylonitrile, polyvinylacetate,cellulose acetate butyrate, nitrocellulose, copolymers ofurethane/carbonate, copolymers of styrene/maleic acid, and mixturesthereof.¹³ Preferably, the biocompatible polymer does not induce chronicinflammation when employed in vivo.

The particular biocompatible polymer employed is not critical and isselected relative to the viscosity of the resulting polymer solution,the solubility of the biocompatible polymer in the biocompatiblesolvent, and the like. Such factors are well within the skill of theart.

Preferred biocompatible polymers include cellulose diacetate andethylene vinyl alcohol copolymer. Cellulose diacetate polymers areeither commercially available or can be prepared by art recognizedprocedures. In a preferred embodiment, the number average molecularweight, as determined by gel permeation chromatography, of the cellulosediacetate composition is from about 25,000 to about 100,000 morepreferably from about 50,000 to about 75,000 and still more preferablyfrom about 58,000 to 64,000. The weight average molecular weight of thecellulose diacetate composition, as determined by gel permeationchromatography, is preferably from about 50,000 to 200,000 and morepreferably from about 100,000 to about 180,000. As is apparent to oneskilled in the art, with all other factors being equal, cellulosediacetate polymers having a lower molecular weight will impart a lowerviscosity to the composition as compared to higher molecular weightpolymers. Accordingly, adjustment of the viscosity of the compositioncan be readily achieved by mere adjustment of the molecular weight ofthe polymer composition.

Ethylene vinyl alcohol copolymers comprise residues of both ethylene andvinyl alcohol monomers. Small amounts (e.g., less than 5 mole percent)of additional monomers can be included in the polymer structure orgrafted thereon provided such additional monomers do not alter thesealing properties of the composition. Such additional monomers include,by way of example only, maleic anhydride, styrene, propylene, acrylicacid, vinyl acetate and the like.

Ethylene vinyl alcohol copolymers are either commercially available orcan be prepared by art recognized procedures. Preferably, the ethylenevinyl alcohol copolymer composition is selected such that a solution of6 weight percent of the ethylene vinyl alcohol copolymer, 35 weightpercent of a tantalum contrast agent in DMSO has a viscosity equal to orless than 60 centipoise at 20° C. As is apparent to one skilled in theart, with all other factors being equal, copolymers having a lowermolecular weight will impart a lower viscosity to the composition ascompared to higher molecular weight copolymers. Accordingly, adjustmentof the viscosity of the composition as necessary for catheter deliverycan be readily achieved by mere adjustment of the molecular weight ofthe copolymer composition.

As is also apparent, the ratio of ethylene to vinyl alcohol in thecopolymer affects the overall hydrophobicity/hydrophilicity of thecomposition which, in turn, affects the relative watersolubility/insolubility of the composition as well as the rate ofprecipitation of the copolymer in an aqueous solution (e.g., blood). Ina particularly preferred embodiment, the copolymers employed hereincomprise a mole percent of ethylene of from about 25 to about 60 and amole percent of vinyl alcohol of from about 40 to about 75. Thesecompositions provide for requisite precipitation rates suitable for usein sealing endoleaks arising from endovascular repair of an abdominalaortic aneurysm.

The term “contrast agent” refers to a biocompatible (non-toxic)radiopaque material capable of being monitored during injection into amammalian subject by, for example, radiography or fluoroscopy. Thecontrast agent can be either water soluble or water insoluble. Examplesof water soluble contrast agents include metrizamide, iopamidol,iothalamate sodium, iodomide sodium, and meglumine.

The term “water insoluble contrast agent” refers to a water insoluble(i.e., has a water solubility of less than 0.01 mg/ml at 20° C.),radiopaque material capable of being monitored during injection into amammalian subject by, for example, radiography or fluoroscopy. Examplesof water insoluble contrast agents include tantalum, tantalum oxide andbarium sulfate, which are commercially available in the proper form forin vivo use. Methods for preparing such water insoluble biocompatiblecontrast agents having an average particle size of about 10 μm or lessare described below. Other water insoluble contrast agents include gold,tungsten and platinum.

The term “biocompatible solvent” refers to an organic material liquid atleast at body temperature of the mammal in which the biocompatiblepolymer is soluble and, in the amounts used, is substantially non-toxic.Suitable biocompatible solvents include, by way of example, ethanol,acetone, dimethylsulfoxide, analogues/homologues of dimethylsulfoxide,ethyl lactate, and the like. Aqueous mixtures with the biocompatiblesolvent can also be employed provided that the amount of water employedis sufficiently small that the dissolved polymer precipitates uponcontact with the blood. Preferably, the biocompatible solvent isdimethylsulfoxide (DMSO).

The term “encapsulation” as used relative to the contrast agent beingencapsulated in the polymer precipitate is not meant to infer anyphysical entrapment of the contrast agent within the precipitate much asa capsule encapsulates a medicament. Rather, this term is used to meanthat an integral coherent precipitate forms which does not separate intoindividual components.

The term “adheres to” as used herein means that the composition formedin situ retains the position/location where the polymer mass formedafter injection and thereby functions to seal the endoleak. This termdoes not necessarily infer that the composition acts as an adhesivealthough in the case of, for example, a cyanoacrylate prepolymer, thesolid composition formed may, in fact, be adhesive.

The term “biocompatible prepolymer” refers to materials which polymerizein situ to form a polymer and which, in the amounts employed, arenon-toxic, chemically inert, and substantially non-immunogenic when usedinternally in the patient and which are substantially insoluble inblood. Suitable biocompatible prepolymers include, by way of example,cyanoacrylates^(14,15,16), hydroxyethyl methacrylate, siliconeprepolymers, and the like. The prepolymer can either be a monomer or areactive oligomer¹⁶. Preferably, the biocompatible prepolymer does notinduce chronic inflammation when employed in vivo.

Compositions

The compositions used in the methods of this invention are fluidcompositions characterized by the fact that these compositions form acoherent mass in vivo which adheres to the vascular and/or prostheticwall at the site of the endoleak thereby sealing the leak. The fluidcompositions employed in the methods of this invention are polymer orprepolymer compositions prepared by conventional methods whereby each ofthe components is added and the resulting composition mixed or stirredtogether until the overall composition is substantially homogeneous.

Fluid polymer compositions preferably comprise a biocompatible polymer,a biocompatible solvent and optionally a contrast agent. Suchcompositions can be prepared by adding sufficient amounts of thebiocompatible polymer to the biocompatible solvent to achieve theeffective concentration for the polymer composition. Preferably, thepolymer composition will comprise from about 2.5 to about 12.0 weightpercent of the biocompatible polymer composition based on the totalweight of the polymer composition and more preferably from about 4 toabout 5.4 weight percent. If necessary, gentle heating and stirring canbe used to effect dissolution of the biocompatible polymer into thebiocompatible solvent, e.g., 12 hours at 50° C.

When employed, sufficient amounts of the contrast agent are then addedto the biocompatible solvent to achieve the effective concentration forthe complete composition. Preferably, the composition will comprise fromabout 10 to about 40 weight percent of the contrast agent and morepreferably from about 20 to about 40 weight percent and even morepreferably about 30 weight percent. Insofar as the contrast agent maynot be soluble in the biocompatible solvent (e.g., a water insolublecontrast agent), stirring is employed to effect homogeneity of theresulting suspension.

In order to enhance formation of the suspension, the particle size ofthe water insoluble contrast agent is preferably maintained at about 10μm or less and more preferably at from about 1 to about 5 μm (e.g., anaverage size of about 2 μm). In one preferred embodiment, theappropriate particle size of the contrast agent is prepared, forexample, by fractionation. In such an embodiment, a water insolublecontrast agent such as tantalum having an average particle size of lessthan about 20 microns is added to an organic liquid such as ethanol(absolute) preferably in a clean environment. Agitation of the resultingsuspension followed by settling for approximately 40 seconds permits thelarger particles to settle faster. Removal of the upper portion of theorganic liquid followed by separation of the liquid from the particlesresults in a reduction of the particle size which is confirmed under anoptical microscope. The process is optionally repeated until a desiredaverage particle size is reached.

When no contrast agent is employed, the biocompatible solvent ispreferably employed at a concentration of from 88 to about 97.5 weightpercent of the biocompatible polymer composition based on the totalweight of the polymer composition and more preferably from about 90 toabout 95 weight percent.

When a contrast agent is employed, the biocompatible solvent ispreferably employed at a concentration of from 52 to 87.5 weight percentbased on the total weight of the composition; more preferably from about54.8 to about 76 weight percent; and even more preferably 64.8 to about66 weight percent. Typical examples of suitable concentrations ofindividual components are given in the table below:

Example Polymer Solvent Contrast Agent A 2.5 weight % 97.5 weight % — B8 weight % 92 weight % — C 2.5 weight % 87.5 weight % 10 weight % D 8weight % 82 weight % 10 weight % E 2.5 weight % 57.5 weight % 40 weight% F 8 weight % 52 weight % 40 weight % G 8 weight % 72 weight % 20weight % H 2.5 weight % 67.5 weight % 30 weight % I 8 weight % 62 weight% 30 weight % J 4 weight % 66 weight % 30 weight % K 5.4 weight % 64.6weight % 30 weight %

The particular order of addition of components to the biocompatiblesolvent is not critical and stirring of the resultingsolution/suspension is conducted as necessary to achieve homogeneity ofthe composition. Preferably, mixing/stirring of the composition isconducted under an anhydrous atmosphere at ambient pressure. Theresulting composition is heat sterilized and then stored preferably insealed amber bottles or vials until needed.

Each of the polymers recited herein is commercially available but canalso be prepared by methods well known in the art. For example, polymersare typically prepared by conventional techniques such as radical,thermal, UV, γ irradiation, or electron beam induced polymerizationemploying, as necessary, a polymerization catalyst or polymerizationinitiator to provide for the polymer composition. The specific manner ofpolymerization is not critical and the polymerization techniquesemployed do not form a part of this invention.

In order to maintain solubility in the biocompatible solvent, thepolymers described herein are preferably not cross-linked.

Prepolymer compositions preferably comprise a biocompatible prepolymerand optionally a contrast agent. When a contrast agent is employed, suchcompositions can be prepared by adding sufficient amounts of thecontrast agent to the solution (e.g., liquid prepolymer) to achieve theeffective concentration for the complete composition. Preferably, theprepolymer composition will comprise from about 10 to about 40 weightpercent of the contrast agent and more preferably from about 20 to about40 weight percent and even more preferably about 30 weight percent. Whenthe contrast agent is not soluble in the biocompatible prepolymercomposition, stirring is employed to effect homogeneity of the resultingsuspension. In order to enhance formation of the suspension, theparticle size of the contrast agent is preferably maintained at about 10μm or less and more preferably at from about 1 to about 5 μm (e.g., anaverage size of about 2 μm).

When the prepolymer is liquid, the use of a biocompatible solvent is notabsolutely necessary but may be preferred to provide for an appropriateviscosity, etc. in the composition. Preferably, when employed, thebiocompatible solvent will comprise from about 30 to about 90 weightpercent of the biocompatible prepolymer composition based on the totalweight of the prepolymer composition and more preferably from about 60to about 80 weight percent. When a biocompatible solvent is employed,the prepolymeric composition typically comprises from about 10 to about50 weight percent of the prepolymer based on the total weight of thecomposition. Typical examples of suitable concentrations of individualcomponents are given in the table below:

Example Prepolymer Solvent Contrast Agent L 100 weight % — — M 90 weight% — 10 weight % N 80 weight % — 20 weight % O 70 weight % — 30 weight %P 60 weight % — 40 weight % Q 70 weight % 30 weight % — R 10 weight % 90weight % — S 60 weight % 30 weight % 10 weight % T 30 weight % 30 weight% 40 weight % U 40 weight % 30 weight % 40 weight % V 60 weight % 10weight % 30 weight %

In a particularly preferred embodiment, the prepolymer is acyanoacrylate ester which is preferably employed in the absence of abiocompatible solvent. When so employed, the cyanoacrylate compositionis selected to have a viscosity of from about 5 to about 20 centipoiseat 20° C.

The particular order of addition of components is not critical andstirring of the resulting suspension is conducted as necessary toachieve homogeneity of the composition. Preferably, mixing/stirring ofthe composition is conducted under an anhydrous atmosphere at ambientpressure. The resulting composition is sterilized and then storedpreferably in sealed amber bottles or vials until needed.

Methods

The compositions described above can then be employed in methods for thecatheter assisted sealing of endoleaks formed by endovascular repair ofan abdominal aortic aneurysm by an endovascular prosthesis.

Specifically, endovascular repair of such aneurysms involves theintroduction of an endovascular prosthesis into the abdominal aorticaneurysm which is an art recognized procedure described, for example, byParodi.¹⁷ This procedure typically consists of dissection of the femoralartery at the groin and introduction of an endovascular prosthesisinside the abdominal aortic aneurysm. Upon insertion, the prosthesisexcludes the aneurysm sac thereby repairing the aneurysm. Suitableendovascular prostheses for endovascular repair of abdominal aorticaneurysms are well known in the art and are described, for example, byBeebe, et al.⁵ Such prostheses, by themselves, do not form part of thisinvention. Similarly, catheters for delivering such endovascularprostheses to the site of the abdominal aortic aneurysm are also wellknown in the art and are commercially available. Such catheters, bythemselves, also do not form part of this invention.

In any event, in the methods of this invention, a sufficient amount ofthe fluid composition described above is introduced at the site of theendoleak via a catheter delivery means preferably under fluoroscopy sothat upon sealing of the endoleak can be visualized. The specific amountof fluid composition employed is dictated by the total size of theendoleak, whether penetration of the fluid composition into the aneurysmis desirable and/or achievable and other factors such as theconcentration of polymer/prepolymer in the composition, the rate ofsolids formation, etc. Such factors are well within the skill of theart.

Prior to sealing the endoleak in the manner described above, theclinician would first identify the site or sites of the endoleak whichtypically include the interface of the aortic wall to the end of theendovascular prosthesis; defects within the endovascular prosthesiswhich permit blood flow through the prosthesis itself; and retrogradeflow from patent lumbar and inferior mesenteric arteries followingplacement of the endovascular prosthesis in the aorta.

Access to these sites of endoleaks can be achieved by microcatheterretrograde access via the patent lumbar and/or inferior mesentericarteries or by direct puncture to the site of the endoleak. After accessis achieved, delivery of the fluid composition proceeds as describedabove.

One particularly preferred method for catheter delivery of thecompositions described in the methods of this invention to the site ofthe endoleak is via a small diameter medical catheter. The particularcatheter employed is not critical provided that polymeric cathetercomponents are compatible with the fluid composition (i.e., the cathetercomponents will not readily degrade in the fluid composition). In thisregard, it is preferred to use polyethylene in the catheter componentsbecause of its inertness in the presence of the fluid compositiondescribed herein. Other materials compatible with the fluid compositionscan be readily determined by the skilled artisan and include, forexample, other polyolefins, fluoropolymers (e.g., Teflon™), silicone,etc.

One particularly preferred method for the catheter injection of thepolymer composition of this invention is described by Greff, et al.,U.S. Pat. No. 5,830,178, which issued on Nov. 3, 1998 and which patentis incorporated herein by reference in its entirety.

When a fluid composition comprising a biocompatible polymer isintroduced at the site of the endoleak, the biocompatible solventdiffuses rapidly into the blood and a solid coherent mass forms in situwhich precipitate is the water insoluble polymer with any contrast agentencapsulated therein. Without being limited to any theory, it isbelieved that initially, a soft gel to spongy solid precipitate formsupon contact with the blood which mass adheres to the vascular orprosthetic wall thereby sealing the endoleak.

When a fluid composition comprising a biocompatible prepolymer isintroduced at the site of the endoleak, the prepolymer polymerizes insitu to form a solid coherent mass or film with any water insolublecontrast agent encapsulated therein. This mass adheres to the vascularand/or prosthetic wall thereby sealing the endoleak.

When a contrast agent is employed, sealing of the endoleak can beconfirmed by injection of an independent contrast agent such iopamidol(50:50 mixture with saline) into the blood flow of the aorta. Failure ofthis contrast agent to reach the aneurysm sac as visualized byfluoroscopy confirms sealing of the endoleak.

The sealing of endoleaks can be conducted during the surgical repair ofthe abdominal aortic aneurysm or in a separate surgical procedureconducted subsequent to the surgical repair. All that is required is thedetermination of the location of the endoleaks in the patient andintroduction of the fluid composition to seal such endoleaks. Inaddition, it is contemplated that the embolization of potential sitesfor leakage including, for example, the patent lumbar and/or inferiormesenteric arteries could be embolize either during or after placementof the endovascular prosthesis.

The methods of this invention are preferably conducted by using kits ofparts comprising two or more of the components necessary to effect theendoleak repair protocol. For example, in one embodiment, this kitcomprises the following components:

(a) a fluid composition which forms a coherent mass in the presence ofblood which mass adheres to the vascular surface and/or the surface ofthe endovascular prosthesis;

(b) a catheter suitable for delivering the fluid composition to anendoleak site formed from endovascular repair of an aneurysm; and

(c) a catheter suitable for delivering an endovascular prosthesis to theaneurysm.

In a preferred embodiment, this kit further comprises an endovascularprosthesis.

In another embodiment, this kit comprises the following components:

(a) a fluid composition which forms a coherent mass in the presence ofblood which mass adheres to the vascular surface and/or the surface ofthe endovascular prosthesis;

(b) a catheter suitable for delivering the fluid composition to anendoleak site formed from endovascular repair of an aneurysm; and

(c) an endovascular prosthesis.

In a preferred embodiment, this kit further comprises a cathetersuitable for delivering an endovascular prosthesis to the aneurysm.

Utility

The methods described herein are useful in reducing or eliminating bloodflow through an endoleak into an endovascularly repaired aneurysmthereby reducing or eliminating the possible rupture of the aneurysm.Accordingly, these methods find use in human and other mammaliansubjects requiring closure of such endoleaks. Additionally, when a waterinsoluble contrast agent is employed, the stability of the closure canbe monitored weeks, months or even years after sealing by non-invasivefluoroscopic techniques. Resealing of the endoleak is also facilitatedby the presence of the water insoluble contrast agent which permits theclinician to readily identify the site of treated endoleaks.

It is contemplated that the procedures set forth above can be employedfor sealing endoleaks arising from insertion of an endovascularprosthesis at vascular sites other than the abdominal aorta. Suchprostheses could be used to repair aneurysms and other vascular diseasesat vascular sites such as peripheral vessels.

The following examples are set forth to illustrate the claimed inventionand are not to be construed as a limitation thereof.

EXAMPLES

Unless otherwise stated, all temperatures are in degrees Celsius. Also,in these examples and elsewhere, the following abbreviations have thefollowing meanings:

atm=atmospheres

cc=cubic centimeter

cm=centimeter

DMSO=dimethylsulfoxide

EVOH=ethylene vinyl alcohol copolymer

g=gram

hrs=hours

im=intramuscularly

in.=inch

IU=international units

IV=intravenously

kg=kilogram

mg=milligram

min.=minute

ML=milliliter

mm=millimeter

PTFE=polytetrafluoroethylene

sec.=seconds

SQ=subcutaneously

μm=micron

Example 1

The purpose of this example is to demonstrate the preparation of a fluidpolymer composition useful in the methods of this invention.

Specifically, an EVOH polymer composition was prepared as follows:

Composition

A) 8 g EVOH;

B) 30 g tantalum having an average particle size of about 3 μm (narrowsize distribution); and

C) 100 mL DMSO.

Component A) was added to Component C) at 50° C. and stirred for 2 hrson a hot plate under an argon blanket. To this resulting composition wasadded Component B and the resulting mixture was mixed until homogeneous.

Example 2

This example illustrates sealing of endoleaks arising from endo-vascularrepair of an abdominal aortic aneurysm in a dog model. The followingillustrates the protocol employed:

Equipment Used

0.035/0.038 3J Guide Wires (Cook, Bloomington, Ind.)

10-14F Introducer Sheaths (Daig, Minnetonka, Minn.)

Angioplasty Balloon Catheters (10×2/ 10'4/ 10'6/ 16'2/ 16×4 18×2/18×4)—(Blue Max and XXL; Meditech, Mass.)

4 mm Aortic Punch (Medtronic, Minneapolis, Minn.)

Palmaz Stents: P4014, P5014 (Johnson and Johnson Interventional Systems,New Jersey)

Infusion Catheters (Easy Rider™ 3F, Micro Therapeutics, Irvine, Calif.)

Microguide Wire (Silver Speed™, Micro Therapeutics, Irvine, Calif.)

Composition of Example I

Contrast Media -Hypaque-76™ (Nycomed, Princeton, N.J.)

7 and 8F Guiding Catheters (Medtronics, Minneapolis, Minn.)

10 mm and 12 mm diameter polyethylene terephthalate Wallgrafts™(Schneider, Boston Scientific, Natick, Mass.)

5F Angiographic Catheters (Cordis, Miami Lakes, Fla.)

Pre-surgical Procedures

The animal was fasted 24 hrs prior to surgery and then pre-anesthetizedwith 0.01 mg/kg Glycopyrrolate SQ followed by anesthetization with acombination of Butorphanol, Xylazine, and Telazol. This combination wasgiven such that 6.6 /kg Telazol is given IM. Next, the animal wasintubated and connected to Isoflurane gas anesthesia of 1-3%.

A 20 gauge catheter was placed into the cephalic vein of the animal and0.9% saline was administered intravenously at a rate of 1-4 mL/kg/hr andthen 15 mL blood was collected for CBC liver profile.

A standard sterile surgical preparation and draping was utilized. Thecarotid or femoral artery was exposed via vessel cutdown and distal andproximal hemostatic loops placed. An arteriotomy was then performed andthe introducer sheath (10-14F) was advanced into the artery lumen. Thesheath and artery was then secured.

After the introducer was placed, the animal was IV heparinized with 100units of heparin/kg of body weight.

A 7-8 F guiding catheter was introduced over a standard 0.035 inch, 3 mm“J” guide wire. A flush anteroposterior projection aortogram wasobtained with use of contrast media, and the mediolateral diameter ofthe dog infrarenal aorta was measured with the use of the markers on thepigtail as standardization. A flat film X-ray was required during thecontrast arteriography.

In accordance of the measurements of the infrarenal aorta, a Palmazstent was deployed into the infrarenal aorta on a 10-16 mm diameter, 4cm long angioplasty balloon with use of fluoroscopic guidance. Then theinfrarenal aortic stent was overdilated to 1.5-2.0 its measured normaldiameter in the dog at 6-8 atm using a standard pressure gauge for asingle inflation lasting 30 sec.

The balloon was removed over a wire and replaced with the measuringpigtail catheter. A repeat aortogram was obtained and the abdominalaortic aneurysm was measured in the animal. A flat film with and withoutcontrast media injections was obtained with all prostheses in the fieldof view.

A Wallgraft was then inserted with the model AAA. Each wallgraft wasmedially perforated with a 4 mm aortic punch which produced a graftdefect that was the source of the endoleak. These endografts were placedcoaxially within the aneurysms.

A repeat aortogram was obtained. A flat film with and without contrastmedia injections was obtained with all prostheses in the field of view.

Upon completion, the arteriotomy was closed with interruptedpolypropylene sutures and the surrounding tissue were sutured. Theanimal was allowed to recover before being returned to a cage.

At the conclusion of surgery, the animal was given approximately 25,000IU/kg procaine and benzathine penicillin SQ.

Post-operatively, the animal received 325 mg/day of aspirin for 6 weeksand ampicillin 1 g/day for 3 days.

Endoleak Treatment

After 1 week, a CT-scan with and without contrast media was performed onthe dog. One major leak at the graft defect (4 mm hole) and another thatinvolved a variable number of lumbar arteries was noted. The animal wasreturned to a second phase of the study.

Treatment of the endoleaks was performed immediately after the CT scan.The animal had been fasted 24 hours prior to surgery and thenpre-anesthetized with 0.01 mg/kg Glycopyrrolate SQ followed byanesthetization with a combination of Butorphanol, Xylazine, andTelazol. This combination was given such that 6.6 mg/kg Telazol is givenIM. Next, the animal was intubated and connected to Isoflurane gasanesthesia of 1-3 %.

A 20 gauge catheter was placed into the cephalic vein of the animal and0.9% saline was administered intravenously at a rate of 1-4 mL/kg/hr.

A standard sterile surgical preparation and draping was utilized. Thecarotid or femoral artery was exposed via vessel cutdown and distal andproximal hemostatic loops placed. An arteriotomy was then performed andthe introducer sheath (10-12F) was advanced into the carotid arterylumen. The sheath and artery were then secured.

After the introducer has been placed, the animal was IV heparinized with100 units of heparin/kg of body weight.

A 7-8 F guiding catheter was introduced over a standard 0.035 inch, 3 mmJ guide wire. A flush anteroposterior projection aortogram was obtainedwith the use of contrast media. The endoleaks were observed. A flat filmX-ray with and without contrast media injections was obtained with theaneurysm in the field of view.

The guiding catheter was removed and a SF guiding catheter was placedadjacent to the 4 mm “hole”. A small amount of contrast was given toconfirm the position of the endoleak.

A microguide wire (0.010 inch) was passed through 5 F catheter andthrough the endograft hole. An infusion microcatheter was positionedover the wire and inside the aneurysm sac and about 1 cc of the fluidcomposition of Example 1 was administered under fluoroscopy untilcomplete seal of the endoleak was achieved with filling of the lumberarteries proximally. Contrast injection confirmed no blood flow throughthis endoleak pathway. Flat films were taken to document the results.

Follow-up aortography and CT scan was performed 5 weeks later,confirming successful treatment of the endoleaks. The above datademonstrates that the methods of this invention effectively sealendoleaks in vivo.

From the foregoing description, various modifications and changes in theabove described methods will occur to those skilled in the art. All suchmodifications coming within the scope of the appended claims areintended to be included therein.

What is claimed is:
 1. A method for sealing endoleaks in a patientarising from endovascular repair of abdominal aortic aneurysms in saidpatient which method comprises: identifying an abdominal aortic apatient; endovascularly repairing said aneurysm by catheter delivery ofan endovascular prosthesis to the site of said aneurysm therebyinhibiting blood flow into the aneurysm; identifying one or moreendoleaks in said patient treated for an abdominal aortic aneurysm witha endovascular prosthesis wherein said endoleak occurs at the theinterface of the aortic wall to the end of the prosthesis or fromdefects within the prosthesis; and delivering through a microcatheter tothe site or sites of said endoleaks a sufficient amount of a fluidcomposition under conditions wherein the fluid composition forms acoherent mass in situ which adheres to the walls of the vascular siteand/or prosthesis thereby sealing the endoleaks.
 2. The method accordingto claim 1 wherein the fluid composition comprises a biocompatiblepolymer and a biocompatible solvent.
 3. The method according to claim 2wherein said biocompatible polymer is selected from the group consistingof cellulose acetate polymers, ethylene vinyl alcohol copolymers andpolyacrylates.
 4. The method according to claim 3 wherein saidbiocompatible polymer is a cellulose acetate polymer or an ethylenevinyl alcohol copolymer.
 5. The method according to claim 2 wherein saidbiocompatible solvent is selected from the group consisting ofdimethylsulfoxide, ethanol, ethyl lactate, and acetone.
 6. The methodaccording to claim 5 wherein said biocompatible solvent isdimethylsulfoxide.
 7. The method according to claim 2 wherein thecomposition further comprises a contrast agent.
 8. The method accordingto claim 7 wherein said contrast agent is a water insoluble contrastagent.
 9. The method according to claim 8 wherein said water insolublecontrast agent is selected from the group consisting of tantalum,tantalum oxide, tungsten, and barium sulfate.
 10. The method accordingto claim 8 wherein said water insoluble contrast agent is characterizedby having an average particle size of about 10 μm or less.
 11. Themethod according to claim 7 wherein said contrast agent is a watersoluble contrast agent.
 12. The method according to claim 11 whereinsaid water soluble contrast agent is selected from the group consistingof metrizamide, iopamidol, iothalamate sodium, iodomide sodium, andmeglumine.
 13. The method according to claim 1 wherein said compositioncomprises a biocompatible prepolymer.
 14. The method according to claim13 wherein said biocompatible prepolymer composition further comprises acontrast agent.
 15. The method according to claim 14 wherein saidcontrast agent is a water insoluble contrast agent.
 16. The methodaccording to claim 15 wherein said water insoluble contrast agent isselected from the group consisting of tantalum, tantalum oxide,tungsten, and barium sulfate.
 17. The method according to claim 15wherein said water insoluble contrast agent is characterized by havingan average particle size of about 10 μm or less.
 18. The methodaccording to claim 14 wherein said contrast agent is a water solublecontrast agent.
 19. The method according to claim 18 wherein said watersoluble contrast agent is selected from the group consisting ofmetrizamide, iopamidol, iothalamate sodium, iodomide sodium, andmeglumine.
 20. The method according to claim 14 wherein thebiocompatible prepolymer is selected from the group consisting ofcyanoacrylates, hydroxyethyl methacrylate and silicon prepolymers.